1. Field of the Invention
The present invention relates to a new method for the diagnosis of inflammatory conditions in the intestines (i.e. small intestines and large intestines (colon and rectum)). The novelty in the method is based on our discovery that nitric oxide (NO) in intestinal gas is a clinically relevant marker for this type of inflammation.
An inflammatory condition in this part of the gastrointestinal tract may be caused by e.g. inflammatory bowel diseases like ulcerative colitis and Crohn's disease, or food intolerance like coeliac disease or food allergy, or e.g. sepsis.
2. Description of the Related Art
It is known that NO is produced at many sites in the gastrointestinal tract and believed to participate in both physiological and pathological events (Whittle G J R, Physiology of the Gastrointestinal Tract, New York: Raven Press (1994) 267-94).
A pathogenic role of NO in ulcerative colitis has been suggested, and patients with active ulcerative colitis exhibit increased mucosal NO synthesis (Middleton et al., Lancet 341 (1993) 465-66; and Boughton-Smith et al., Lancet 342 (1993) 338-40). However, the cited studies were performed in vitro and used indirect citrulline assays to measure NO-synthase activity in biopsies taken from both colonic and rectal mucosa. The studies did not account for in what layer of the intestinal mucosa the activity was located. It is likely that NO formed in the mucosa would have a tendency to diffuse towards the intestinal lumen, but in order to reach there, NO has to be produced in the superficial layers including epithelial cells, intraepithelial cells and luminal cells like e.g. phagocytes. In case this highly reactive species is produced deeper in the mucosal layer, it will be destroyed during its diffusion route. Results presented herein show for the first time that NO-synthase activity in intestinal inflammatory disease is located in the epithelial cell layer next to the lumen of the colon and rectum.
It is recognized that intestinal bacterias exist that are able to convet small amounts of nitrite to NO (Ji et al. Biochem. Arch. 5 (1989) 61-66).
With respect to the airways, alterations in NO concentrations in exhaled breathing air have been found for inflammatory conditions (Alving et al., WO 9502181; Alving et al., Eur. Resp. J. 6 (1993) 1368-70; Hamid et al., Lancet 342 (1993) 1510-13; Karithonov et al., Lancet 343 (1994) 133-135; and Persson et al., Lancet 343 (1994) 146-147. Increased levels of NO have also been found in regurgitated air (Alving et al., WO 9502181; and Lundberg et al., Gut 35 (1994) 1543-1546). A somewhat different approach for the measurement has lead to suggestions that NO in exhaled breathing air originates from the lung (Gustafsson, WO-A-9305709 and SE-A-91032433).